Coagulation Assessment - Exam IV Flashcards
1
Q
What is Hemostasis?
A
Normal hemostasis is a balance btw clot generation, thrombus formation, andregulatory mechanisms that inhibit uncontrolled thrombogenesis
2
Q
The goals of hemostasis are:
A
- to limit blood loss from vascular injury
- maintain intravascular blood flow
- promote revascularization after thrombosis
3
Q
2 stages of hemostasis:
A
Primary Hemostasis:Immediateplatelet deposition at the endovascular injury site
- Leads to the initial platelet plug formation
- Only adequate for minor injury
Secondary Hemostasis: clotting factors activated
- Stabilized clot formed and secured with crosslinked fibrin
4
Q
What is vascular endothelial role?
A
Vascular endothelial cells have antiplatelet, anticoagulant, and fibrolytic effects to inhibit clot formation
5
Q
Anti-clotting mechanisms of the endothelial cells:
A
- are negatively charged to repel platelets
- produce platelet inhibitors such as prostacyclin and nitric oxide
- excrete adenosine diphosphatase, which degrades adenosine diphosphate (ADP), a platelet activator
- increase protein C, an anticoagulant
- produce Tissue Factor Pathway Inhibitor (TFPI), which inhibits factor Xa & TF-VIIa complex
- Synthesize tissue plasminogen activator (t-PA)
6
Q
Where are Plt derived from?
A
Derived from bone-marrow megakaryocytes
7
Q
What is the lifespan of inactive plts?
A
inactive plts circulate as disc-shaped anuclear cells with a lifespan of 8-12 days
8
Q
__% of plts are consumed to support vascular integrity with ___ - ___ billion new plts formed daily.
A
Normally, approx 10% of platelets are consumed to support vascular integrity with 120-150 billion new platelets formed daily
9
Q
What increases the membrane surface area of plts?
A
The platelet membrane contains numerous receptors and a surface canalicularsystem, which increases membrane surface area
10
Q
3 phases alterations of plts upon exposure to contents in the ECM?
A
Upon exposure to contents in the ECM, platelets undergo 3 phases of alteration:
adhesion
activation
aggregation
11
Q
What are the contents of the underlying extracellular matrix? When does this happen?
A
Damage to endothelium exposes the underlying extracellular matrix (ECM), which contains collagen, von Willebrands factor, and other glycoproteins
12
Q
When does Adhesion happen?
A
occurs upon exposure to Extracellular matrix proteins
13
Q
What causes the release of granular contents from plts? What is this called?
A
Activation:stimulated when platelet interacts w/collagen & tissue factor (TF), causing the release of granular contents
14
Q
What are the 2 types of storage granules?
A
alpha granules and dense bodies
15
Q
What do Alpha granules contain?
A
Alpha granules: contain fibrinogen, factors V & VIII, vWF, Plt-derived growth factor & more
16
Q
What do dense bodies contain?
A
Dense bodies: contain ADP, ATP, calcium, serotonin, histamine, epinephrine
17
Q
What is Aggregation?
A
occurs when the granular contents are released, which activate additional platelets, propagating plasma-mediated coagulation
18
Q
Each stage of the clotting cascade requires assembly of membrane-bound activated tenase-complexes
- each complex is composed of : 4?
A
1) a substrate (inactive precursor)
2) an enzyme (activated coagulation factor)
3) a cofactor (accelerator or catalyst)
4) calcium
19
Q
What is the extrinsic pathway, hemostasis?
A
The Extrinsic pathway is the initiation phase of plasma-mediated hemostasis
20
Q
What begins the final common pathway?
A
Factor Xa begins the final common pathway
21
Q
Start of the extrinsic pathway to the final common pathway?
A
- Begins endothelial injury, exposing TF to the plasma
- TF forms an active complex with VIIa (TF/VIIa complex)
- TF/VIIa complex binds to and activates factor X, converting it to Xa
- TF/VIIa complex also activates IX→ IXa in the intrinsic pathway
- IXaand calcium convert factor X to Xa (intrinsic pathway)
- Factor Xa begins the final common pathway
22
Q
Intrinsic pathway begins with what factor?
A
Beginning w/XIIa, it was initially thought to occur only in response to endovascular contact with negatively-charged substances (glass, dextran)
23
Q
What kind of role does the intrinsic pathway play in hemostasis?
A
the intrinsic pathway plays a minor role in theinitiation of hemostasis, and is more an amplification system to propagate thrombin generation initiated by the extrinsic pathway
24
Q
Intrinsic pathway hemostasis initiation steps?
A
- Intrinsic pathway hemostasis initiation
- Upon contact with a negatively charged surface, factor XII becomes activated
- Factor XIIa converts XI to XIa
- (XIa + VIIIa +plt-membrane phospholipid + Ca++) converts factor X to Xa
- Xa initiates the final common pathway
25
Intrinsic pathway propagation steps?
- Activated Thrombin (IIa) activates factors V, VII, VIII, XI to amplify thrombin generation
- This process activates the platelets, leading to propagation of the FCP
26
What is the prothrombinase complex?
Factor X becomes Xa and binds with Va to form a "prothrombinase complex."
Both intrinsic and extrinsic tenase-complexes facilitate the formation of prothrombinase complexes
27
Common pathway steps?
Prothrombinase complex rapidly converts prothrombin (II) into thrombin (IIa)
Thrombin attaches to the platelets and converts fibrinogen (I) to fibrin (Ia)
Fibrin molecules crosslink to form a mesh that stabilizes the clot
28
How is a basic clot formed from thrombin?
Thrombin cleaves fibrinopeptides from fibrinogen to generate fibrin, which polymerizes into strands to form basic clot
29
What is the final step in thrombin generation?
- factor XIIIa crosslinks the fibrin strands to stabilize and make an insoluble clot, resistant to fibrinolytic degradation
-Thrombin generation is the key-step in regulating hemostasis
30
What depicts thrombin generation and fibrin formation?
Common pathway
31
What does prothrombinase complex do in the clotting cascade?
Prothrombinase Complex converts PT (II) into thrombin (IIa)
32
What are the four coagulation counter-mechanisms?
- Fibrinolysis
- Tissue factor pathway inhibitor (TFPI)
- Protein C system
- Serine Protease Inhibitor (SERPINs)
33
What are considered SERPINs?
- Antithrombin (AT) : inhibits thrombin, Factors 9a, 10a. 11a, 12a
- Heparin : binds to AT, causing a conformational change that accelerates AT activity
- Heparin coFactor II - Inhibits thrombin alone
34
What is fibrinolysis?
endovascular TPA & urokinase convert plasminogen to plasmin
Plasmin breaks down clots enzymatically, and degrades factors V & VIII
35
What is tissue factor pathway inhibitor?
forms complex w/Xa that inhibits TF/7a complex, along with Xa; thereby downregulating the extrinsic pathway
36
Protein C system?
inhibits factors 2 (II), 5a (Va) & 8a (VIIIa)
37
If bleeding disorder suspected: standard first-line labs?
*If bleeding disorder suspected: PT, aPTT are standard first-line labs
38
Blood thinners in Pre-op Assessment?
ASA, NSAIDS, Vitamin E, Ginko, Ginger, Garlic supps
39
Common coexisting disease with coagulation dysfunction?
Coexisting dz s/a renal, liver, thyroid & bone marrow disorders
40
General pre-op assessment?
- Preop identification & correction of hemostatic disorders is vital
- A carefully performed bleeding hx is the most effective predictor of bleeding
- Inquire about frequent nose bleeds, bleeding gums, easy bruising
- Ask about any h/o excessive bleeding w/dental extractions, surgery, trauma, childbirth & blood transfusion
- Is there a family history of bleeding disorders?
41
Bleeding Disorders (7)
Von Willebrand's
Hemophilia
Drug-induced bleeding
Liver disease
Chronic renal disease
Disseminated Intravascular Coagulation
Trauma-induced coagulopathy
42
What is the most common inherited bleeding disorder?
Von Willebrand's Disease
43
What % of the population has Von Willebrand's Disease?
Effects 1% of population
44
What does a deficiency in vWF do to plts?
Deficiency in vWF, causing defective plt adhesion/aggregation
45
What roles does vWF play in plt?
vWF plays critical role in plt adhesion & prevents degradation of factor 8 (VIII)
46
What labs may be normal in vWF?
Platelets & PT will be normal; aPTT might be prolonged d/o level of factor 8
Routine coagulation labs generally not helpful
47
What are the appropriate lab exams for diagnosis of vWF?
Better tests: vWF level, vWF-plt binding activity, Factor 8 level, Plt function assay
Mild vWD often responsive to DDAVP (↑s vWF)
48
How to treat bleeding in the OR for a patient with vWF?
Intraop bleeding may require administration of vWF & Factor 8 concentrates
49
Hemophilia A & B factor deficiency?
Hemophilia A: factor 8 (VIII) deficiency; occurs 1 in 5,000
Hemophilia B: factor 9 (IX) deficiency; occurs 1 in 30,000
2/3 genetically inherited, 1/3 present as new mutation w/o family hx
50
What blood products should be ready before surgery for hemophilia patients?
DDAVP and Factors 8 and/or 9 may be indicated before surgery
51
What is commonly seen in children with hemophilia?
Frequently presents in childhood as spontaneous hemorrhage involving joints & muscles.
52
Lab considerations for hemophilia?
Labs show normal PT, Plts, bleeding time
PTT normally prolonged
53
What medications can cause drug-induced bleeding?
Heparin
Warfarin
Direct Oral Anticoags (DOACs)
Beta-Lactam Abx
Nitroprusside
NTG
NO
SSRIs
54
What supplements that can induce bleeding?
cayenne
garlic
ginger
ginkgo biloba
vitamin E
tumeric
st. john's wort
grapeseed oil
55
What factors are synthesized by the liver?
Liver is primary source of factors 5, 7, 9, 10, 11, 12 (V, VII, IX, X, XI, XII)
along with proteins C & S, and antithrombin
56
What are 3 hemostatic issues stem from liver disease?
Impaired synthesis of coagulation factors
Quantitative and qualitative platelet dysfunction
Impaired clearance of clotting and fibrinolytic proteins
57
What are valuable guides in liver disease for coagulation?
TEG & Rotational Thromboelastometry (ROTEM) are valuable guides
58
How does chronic liver disease affect coagulation?
Chronic liver pts often display a rebalanced hemostasis as well as sufficient amounts of thrombin production
Chronic liver dz=compensated but not optimal.
59
What labs are often seen prolonged in liver disease?
Lab findings often show prolonged PT and possible prolonged PTT
However, values only reflect the lack of pro-coagulation factors, not accounting for the concurrent lack of anticoagulation factors
60
CKD patients display a baseline anemia. Is this due to?
Lack of erythropoietin
Platelet dysfunction (due to uremic environment)
61
What may cause shortened bleeding times in chronic renal disease patients?
Dialysis and correction of anemia
62
Tx of platelet dysfunction in CKD patients includes:
Cryoprecipitate (rich in vWF)
DDAVP
Conjugated estrogens given pre-operatively x 5 days
**Plt dysfunction may lead to thrombosis or increased bleeding
63
What is Disseminated Intravascular Coagulation?
Pathological hemostatic response to TF/7a complex causing excessive activation of the extrinsic pathway, which overwhelms the anticoagulant mechanisms and generates intravascular thrombin
Coagulation factors & platelets become depleted during widespread microvascular thrombotic activity, causing multi-organ dysfunction
64
DIC may be precipitated by?
trauma, amniotic fluid embolus, malignancy, sepsis, or incompatible blood transfusion
65
Lab findings for DIC?
Lab findings:↓Plts, prolonged PT/PTT/Thrombin time,↑soluble fibrin & fibrin degradation products
66
DIC Mgmt?
Mgmt: Correct underlying condition, administration of appropriate blood products
67
What is the common cause of trauma-related death?
Uncontrolled hemorrhage is a common cause of trauma-related death.
68
Do coagulopathies occur due to?
Coagulopathies occur due to: acidosis, hypothermia and/or hemodilution
69
Trauma Induced Coagulopathy (TIC):
- Acute coagulopathy seen in trauma pts, which is thought to be related to activated protein C decreasing thrombin generation
- Hypoperfusion is thought to be the driving factor for protein C activation
- The endothelial glycocalyx, which contains proteoglycans, degrades
- Proteoglycan-shedding results in "auto-heparinization"
- Platelet dysfunction contributes to the increased bleeding
70
What is the most common cause of inherited prothrombotic disease?
The most common inherited prothrombotic diseases are caused by a mutation in factor V or prothrombin
71
Factor V Leiden mutation leads to? - present in __% caucasian population
Factor V Leiden mutation leads to activated protein C resistance;
present in 5% caucasian population
72
Prothrombin mutation causes?
causes ↑PT concentration, leading to hypercoagulation
73
What is Thrombophilia?
inherited or acquired predisposition for thrombotic events
- Generally, manifests as venous thrombosis
- Highly susceptible to Virchow's Triad (blood stasis, endothelial injury, hypercoagulability)
74
What is antiphospholipid Syndrome?
Autoimmune disorder w/antibodies against the phospholipid-binding proteins in the coagulation system.
Characterized by recurrent thrombosis and pregnancy loss
Often require life-long anticoagulants
75
What causes an increases risk of thrombosis?
Oral contraceptives, pregnancy, immobility, infection, surgery & trauma greatly increase the risk of thrombosis in these populations.
76
What is Heparin-Induced Thrombocytopenia?
How many days after heparin tx does it usually occur?
Mild-moderate thrombocytopenia associated w/Heparin
occurs 5-14 days after heparin tx
77
HIT: % of patients that have an autoimmune response?
Autoimmune response occurring in up to 5% pts receiving heparin
78
What does HIT result in?
Results in platelet count reduction as well as activation of the remaining platelets and potential thrombosis
79
Risk factors for HIT?
Risk factors: women, pts receiving high heparin doses such as w/CPB
Unfractionated heparin carries greater rx than LMWH
80
If HIT is suspected?
If HIT suspected: D/C heparin, convert to an alternative anticoagulant
Warfarin is contraindicated bc it decreases protein C & S synthesis
81
How is HIT diagnosis confirmed?
HIT diagnosis confirmed with HIT antibody testing
Antibodies are typically cleared from circulation in 3 months
82
If pt has received a prior heparin dose, _______ or ____ may occur within __ day of subsequent dose?
If pt has received a prior heparin dose, thrombocytopenia or thrombosis may occur within 1 day of subsequent dose
83
What are the Coagulation labs?
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT)
Anti-factor Xa activity assay
Platelet Count
Activated Clotting Time (ACT)
Heparin Concentration Measurement
Viscoelastic Coagulation Tests
84
What does Viscoelastic Coagulation Test measure?
Viscoelastic Coagulation Tests: Measures all aspects of clot formation from early fibrin generation to clot retraction & fibrinolysis. Coagulation diagrams generated.
Allows for more precise blood product administration
TEG (Thromboelastogram)
ROTEM (Rotational Thromboelastometry)
85
What Heparin Concentration Measurement determine?
determines perioperative heparin concentration
1mg protamine will inhibit 1mg heparin
As increasing amounts of protamine are added to heparinized blood, time to clot decreases until protamine concentration > heparin concentration
Estimates of plasma heparin concentration
86
Activated Clotting Time (ACT) addresses what pathways?
Addresses intrinsic and common pathways
87
ACT normal value?
Normal = 107 +/- 13 seconds
88
What does ACT measure?
- Used to measure responsiveness to heparin
- Variation of whole blood clotting time, with the addition of a clotting activator to accelerate clotting time
- POC analyzers available
89
What is Platelet Count considered? normal values?
Standard component of coagulation testing
Normal = Plt count >100,000 plts/microliter
POC testing is available
90
Anti-factor Xa activity assay? Provides functional assessment of what? Can be used to assess what medications?
Plasma combined w/Xa and an artificial substrate that releases a colorimetric signal after factor Xa is cleaved
Provides functional assessment of heparin's anticoagulant effect
Can also be used to assess effect of
LMWH, Fondaparinux, factor Xa inhibitors
91
Antiplatelet Agents?
Inhibit platelet aggregation and/or adhesion
92
3 main classes of antiplatelet agents?
- Cyclooxygenase Inhibitors
- P2Y12 receptor antagonists
- Platelet GIIb/IIIa R antagonists
93
Platelet GIIb/IIIa R antagonists prevents what?
Platelet GIIb/IIIa R antagonists: prevent vWF & fibrinogen from binding to GIIb/IIIa-R
Abciximab, Eptifibatide, Tirofiban
94
P2Y12 receptor antagonists inhibits what? What medications are these?
Inhibit P2Y12-R→preventing GIIb/IIIa expression
Clopidogrel: anti-plt effects x 7 days after d/c
Ticlopidine: anti-plt effects x 14-21 days after d/c
Ticagrelor & Cangrelor: Short-acting, <24h activity
95
Cyclooxygenase Inhibitors: blocks what? Medications under this class?
Block Cox 1 from forming TxA₂, which is important in plt aggregation
ASA: anti-plt effects x 7-10 days after d/c
NSAIDS: anti-plt effect x 3 days
96
Anticoagulant: most common?
Warfarin (Most common)
97
Vitamin K antagonists (anticoagulants) ?
Inhibit synthesis of Vit-K dependent factors 2, 7, 9, 10, Protein C & S
98
Warfarin is used to treat what diseases? Lab considered? Reversible?
DOC for valvular Afib & valve-replacements
Long HL (40h), can take 3-4 days to reach therapeutic INR (2-3)
Usually requires heparin until therapeutic effect achieved
Frequent lab monitoring required (PT/INR)
Reversable w/Vitamin K
99
How does heparin work?
Binds to antithrombin→ directly inhibits soluble (IIa, just free-floating in plasma) thrombin and Xa
100
Unfractionated heparin? Half life? Reversible?
Unfractionated Heparin
Short HL, given IV
Fully reversable w/Protamine
Close monitoring required
101
LMWH? Half life? Coag testing? Reversible?
Longer HL, dosed BID SQ
No coag testing needed
Protamine only partially effective
102
Fondaparinux? Half life? Reversable?
Much longer HL (17-21h), dosed once/day
Protamine not effective.
Fondaparinux is a selective factor Xa inhibitor (indirect) d/t binding directly to antithrombin and enhances its ability to inactivate Factor Xa,
103
What was the first anticoagulant drug?
Dabigatran (Pradaxa): 1st DOAC
Director Thrombin Inhibitor approved for CVA prevention and non-valvular A-fib
104
Direct Thrombin Inhibitors: block what?
bind/block thrombin in both soluble & fibrin-bound states
105
What are Direct Thrombin Inhibitor medications?
Hirudin:
Argatroban:
Bivalirudin:
Dabigatran (pradaxa):
106
Hirudin is naturally found in?
Leeches
107
Argatroban: Half life? Labs to consider? MOA?
synthetic
reversibly binds to thrombin.
HL 45 min.
Monitored intraop w/PTT or ACT
108
Bivalirudin? Used with what patients? Half life?
synthetic,
shortest HL of DTI’s
DOC for renal or liver impairment
109
Direct Xa Inhibitors:
Rivaroxaban (Xarelto), Apixaban (Eliquis), Edoxaban (Savaysa)
110
Direct Oral Anticoagulants (DOACs):
newer class, introduced over the past 10 yrs
Have more predictable pharmacokinetics/dynamics
Fewer drug interactions
Dosed daily w/o lab monitoring
Fewer embolic events, intracranial hemorrhages, and lower mortality than warfarin
111
Direct Oral Anticoagulants: HL? efficacy?
Efficacy similar to Warfarin, but much shorter HL
112
Thrombolytics used to? MOA?
Used to dissolve blood clots
May be given IV or directly into site of blockage
Most are serine proteases that convert plasminogen to plasmin, which breaks down fibrinogen to fibrin
113
2 categories of thrombolytics?
2 categories:
Fibrin-Specific: Altepase (tPA), Reteplase, Tenecteplase
Non-Fibrin-Specific: Streptokinase * not widely used d/t allergic reactions
114
Are thrombolytics and surgery contraindicated?
*Surgery is contraindicated within 10 days of thrombolytic tx
115
Procoagulants?
Used to mitigate blood loss
116
Categories of procoagulants?
2 classes→Antifibrinolytics & Factor Replacements
117
Antifibrinolytics: subclasses?
Lysine analogues & a SERPIN
118
Lysine analogues: meds & MOA?
Lysine analogues: Epsilon-amino-caproic acid (EACA) & Tranexamic Acid (TXA)
Binds & inhibits plasminogen from binding to fibrin→impairing fibrinolysis
119
Antifibrinolytic: SERPIN?
SERPIN: Aprotinin (removed from market d/t renal & cardio toxicity)
120
what are the Factor Replacements? (4)
Recombinant VIIa (rfVIIa)
Prothrombin (PCC)
Fibrinogen concentrate
FFP & Cyroprecipitate
121
Prothrombin Complex Concentrate (PCC) contains?
contain vitamin-K factors
122
RfVIIa?
↑’s thrombin generation via intrinsic & extrinsic paths
123
Fibrinogen concentrate derived from?
derived from pooled plasma. Standard concentration.
124
Cryoprecipitate & FFP: contains more but less what?
Cheaper & contain more coag factors, but less specific composition
125
Preop guidelines for anticoagulants for Warfarin?
low rx pts should d/c 5 days prior to surgery & restart 12-24h postop
high rx pts should stop 5 days prior & bridge w/UFH or LMWH
126
Preop guidelines for anticoagulants heparin?
UFH should be d/c’d 4-6h prior to surgery & resumed (no bolus) ≥12h postop
LWMH should be d/c’d 24h prior to surgery & resumed 24h postop
127
Preop guidelines for anticoagulants: Aspirin?
not as defined
mod/high rx pts- current recommendation is to continue ASA
low rx pts- stop 7-10 days prior to surgery
128
Preop guidelines for anticoagulants: Pts post coronary stent placement?
Bare-metal stents→ delay elective surgery 6 weeks after placement
Drug-eluding stents→ delay elective surgery 6 months after placement
129
Emergent Reversal of Anticoags: Warfarin reversal?
may be required for excessive bleeding or emergent surgery
Prothrombin Complex Concentrates: DOC for emergent coumadin reversal
though HL is short
Vit K to restore liver carboxylation of vit K-dep factors for more sustained correction
130
Emergent Reversal of Anticoags: DOAC Factor Xa Inhibitors?
may be reversed by Andexanet, a derivative of factor Xa
131
Emergent Reversal of Anticoags: Direct Thrombin Inhibitors?
No reversal for most, however, HL relatively short
The DOAC Dabigatran (Pradaxa) does have an antidote –Idarucizumab
